KFO309 - The clinical research unit Virus Induced Lung injury

Principal Investigators

István Vadász

Dr. med. István Vadász

Justus Liebig University
Department of Internal Medicine
Klinikstr. 33; 35392 Giessen

+49-641-985-56763
Christos Samakovlis

Prof. Dr. Christos Samakovlis

Justus Liebig University
Department of Molecular Pneumology
Aulweg 130; 35392 Giessen

+49-641-99-39395

Role and regulation of alveolar protein clearance in influenza virus-induced lung injury

Summary

Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) pneumonia and is characterized by disruption of the alveolar epithelial barrier leading to accumulation of protein-rich alveolar edema, which if not resolved promotes deleterious alveolar remodeling leading to poor outcome. Of note, non-survivors of ARDS exhibit three-fold higher levels of protein in their edema fluid than survivors of the disease. However, the molecular mechanisms of alveolar protein removal remain incompletely understood. Importantly, many of the trafficking and repair mechanisms are evolutionary conserved and can be detected in Drosophila airways, which therefore served as a high throughput screening tool. 
In the first funding period, we have been focusing on the mechanisms by which IV infection impairs alveolar protein clearance. We have established and used various in vivo and in vitro model systems, including a mouse model of acute lung injury (ALI) secondary to IV infection, mouse and human three-dimensional precision cut lung slices (PCLS) and a newly established human epithelial air-liquid interface cell culture model allowing IV infection. We have discovered that the TGF β/GSK3 β/megalin axis is markedly compromised upon IV infection, leading to inhibition of alveolar protein clearance in mouse models and, in a translational approach, in human disease, based on sample analyses from patients with IV-induced ARDS. In parallel, we have defined a novel, highly conserved regulatory circuit that centrally controls activation of endocytosis and luminal clearance of macromolecules in Drosophila airways. This circuit involves two type III receptor tyrosine phosphatases (Ptps), the non-receptor tyrosine kinase Btk29A and the actin nucleation-promoting factor Wiskott-Aldrich syndrome protein and SCAR homologue (WASH), the defining member of a protein complex required for endosomal vesicle traffic. Most importantly, the Btk/WASH system appears to be centrally involved in uptake of IV particles in both murine and human epithelial cells. As both propagation of IV infection and clearance of protein-rich pulmonary edema secondary to IV-induced lung damage are mediated by alveolar epithelial endocytic processes, we aim to specifically and selectively target each endocytic process in the upcoming funding period. We envision to inhibit epithelial viral entry by blocking the Btk/WASH cascade, while upregulating protein clearance by interfering with distal elements of the TGF β/GSK3 β/megalin axis. Moreover, we aim to identify putative regulators of the endocytic routes driving IV and protein uptake and manipulate them in translationally relevant model systems that we established during the first funding period. Ultimately, we envision defining novel therapeutic strategies to selectively inhibit viral uptake and spread while improving alveolar clearance of excess protein and thereby the outcome in IV-ARDS.

Publications

Anti-anabolic Effects of Hypercapnia - No Country for Strong Men

Am J Respir Cell Mol Biol 2019 Jul 10 Epub ahead of print


The role of CD36 in endothelial albumin transcytosis

Am J Physiol Lung Cell Mol Physiol 2019 316(5):L738-L739.


















Principal Investigators

István Vadász

Dr. med. István Vadász

Justus Liebig University
Department of Internal Medicine
Klinikstr. 33; 35392 Giessen

+49-641-985-56763
Christos Samakovlis

Prof. Dr. Christos Samakovlis

Justus Liebig University
Department of Molecular Pneumology
Aulweg 130; 35392 Giessen

+49-641-99-39395

Project group

  • Ramesh Kumar Krishnan

    Dr. Ramesh Kumar Krishnan

    Postdoc

  • Janine Koepke

    Dr. Janine Koepke

    Postdoc

  • Athanasios Physikopoulos

    Dr. Athanasios Physikopoulos

    Postdoc

  • Luciana C. Mazzocchi

    Dr. Luciana C. Mazzocchi

    Postdoc

  • Vitalii Kryvenko

    Vitalii Kryvenko

    PhD student

  • Andrés Alberro

    Andrés Alberro

    PhD student

  • Miriam Wessendorf

    Miriam Wessendorf

    Technician